Heterotrimeric G proteins are signal transducers for many hormones, neurotransmitters, growth factors, and chemotactic factors. We have discovered a family of proteins termed RGSs that impairs signal transduction through pathways that utilize heterotrimeric G proteins. There are at least 16 members of the RGS family and they are expressed in a wide variety of cell types. Some are tissue specific while others are broadly expressed. These proteins are highly conserved evolutionarily as they are the functional and structural homologs of the yeast protein Sst2p. Introduction of the mammalian proteins into yeast can impair signal transduction through a G protein linked pathway in yeast in a manner analogous to Sst2p. Epistatic studies in yeast indicate that the RGS family members require the Galpha subunit in order to function. We have isolated complete cDNAs for three family members and partial sequences for three other members. Besides impairing G protein signaling in yeast the introduction of RGS family members into mammalian cells also impairs signaling through G protein coupled receptors. In addition, signaling through G protein coupled receptors can be a strong inductive signal for RGS production suggesting that these proteins can function in a feedback mechanism to limit signal transduction through these receptors. We have produced recombinant RGS1, RGS3, and RGS4 for protein interaction studies and for the development of specific antisera. Large scale production of RGS1 for structural studies is in progress. The RGS family members specifically interact with the Galpha subunit of the heterotrimeric G protein and they interfere with the exchange of GDP for GTP. Individual RGS family members may interact with several different Galpha subunits although they do so with varying affinities. Transgenic mice that over express RGS1 in B lymphocytes have been developed and are currently being analyzed. Mouse genomic clones have been isolated for three RGS family members and gene targeting experiments are in progress to assess the physiologic roles of these genes. Our current thinking is that these proteins modulate and fine tune G protein signaling and individual RGS members may modulate a specific G protein or class of G proteins. As such the RGSs offer potential targets for drug development.